The overall objective of this project is to investigate genetic factors involved in specific subtypes of dyslexia and dysgraphia by evaluating kindreds whose members have been well-characterized for learning disabilities (LD). Four lines of evidence support the hypothesis that there is a genetic contribution to LD: 1) individuals with dyslexia cluster in families; 2) the concordance for dyslexia is greater in monozygotic twins that in dizygotic twins; 3) segregation analysis of family pedigree data has found evidence for both major locus and polygenic transmission; 4) genetic linkage analyses have identified regions of the genome that are nonrandomly associated with LD. The exact role of genes in these disorders in unknown and patterns of inheritance, gene-gene interactions and gene-environment interactions are likely to be complex. Recent advances in molecular genetic methodology combined with improved approaches to statistical analysis make it possible to identify genetic factors in complex disorders. LD is a heterogeneous group of disorders with a spectrum of phenotypes. Individuals can have dyslexia alone, dysgraphia alone or a combination of both disabilities. These disabilities can be further subdivided by the specific processing deficit involved; individuals may be orthographically impaired, phonologically impaired or have a combination of both deficits. Furthermore, the deficit in dyslexia may be rule- governed or word-specific. In addition, dyscalculia may or may not be found in combination with the other disabilities. It is not known whether these LD subtypes are genetically distinct or whether they represent different manifestations of the same genetic defect. There is evidence that chromosomes, 1, 6 and 15 may contain genes involved in LD. Linkage studies that resulted in these localizations were performed on subject populations that were not categorized by LD subtype. We propose to evaluate the genetic distinction between dyslexia and dysgraphia, between orthographic and phonologic processing disabilities and between word-specific and rule-governed deficits. In collaboration with the Clinical and Statistical Cores, Project 3 will (a) receive and process blood samples from subjects and family members, prepare and store DNA and establish lymphoblastoid cell lines (b) confirm the published linkage associations to markers on chromosomes 1, 5 and 15, (c) investigate genetic heterogeneity and map other genes involved in LD. This will be accomplished by genotyping DNA samples for highly polymorphic short tandem repeat markers. Pedigree data will be evaluated to determine possible modes of transmission of LD. To detect sites of LD genes, genotype data will be analyzed using linkage analysis and non- parametric methods. Once regional localizations are identified, the map locations of the genes will be refined to enable positional cloning.